Hydrochloride salts of 5-[4-[2-(n-methyl-n-(2-pyridyl) amino)ethoxy]benzyl]thiazolidine-2,4-dione

ABSTRACT

A substantially non-hydrated and non-hygroscopic or slightly hygroscopic hydrochloride salt of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione; a pharmaceutical composition containing such a compound, a process of preparing such a compound and the use of such a compound in medicine.

[0001] This invention relates to a novel pharmaceutical, to a processfor the preparation of the pharmaceutical and to the use of thepharmaceutical in medicine.

[0002] European Patent Application, Publication Number 0,306,228 relatesto certain thiazolidinedione derivatives disclosed as havinghypoglycaemic and hypolipidaemic activity. The compound of example 30 ofEP 0,306,228 is5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione(hereinafter also referred to as “Compound I”).

[0003] International Patent Application, Publication Number WO94/05659discloses certain salts of the compounds of EP 0,306,228 and inparticular the maleic acid salt.

[0004] It has now been discovered that Compound I forms a novel,non-solvated hydrochloride salt (hereinafter also referred to as the“Hydrochloride”) that is particularly stable and hence is suitable forbulk preparation and handling. Surprisingly the Hydrochloride isindicated to be non-hygroscopic and shows good aqueous solubility.Moreover, the Hydrochloride is stable in aqueous solution and does notdissociate therein. It can also be prepared by an efficient, economicand reproducible process particularly suited to large-scale preparation.

[0005] The novel Hydrochloride also has useful pharmaceutical propertiesand in particular it is indicated to be useful for the treatment and/orprophylaxis of diabetes mellitus, conditions associated with diabetesmellitus and certain complications thereof.

[0006] Accordingly, the present invention provides5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,hydrochloride characterised in that it:

[0007] (i) provides an infrared spectrum containing peaks at about 1745,1516, 1257, 1056 and 803 cm⁻¹;

[0008] (ii) provides an X-ray powder diffraction (XRPD) patterncontaining peaks at about 10.1, 13.4, 17.2, 22.2 and 29.4 °2θ; and/or

[0009] (iii) provides a Raman spectrum containing peaks at about 1314,1242, 1185, 918 and 404 cm⁻¹.

[0010] In one favoured aspect, the Hydrochloride provides an infraredspectrum substantially in accordance with FIG. I.

[0011] In one favoured aspect, the Hydrochloride provides an X-Raypowder diffraction pattern (XRPD) substantially in accordance with FIG.II.

[0012] In a further aspect, the Hydrochloride provides a raman spectrumsubstantially in accordance with FIG. III.

[0013] The present invention encompasses the Hydrochloride isolated inpure form or when admixed with other materials.

[0014] Thus in one aspect there is provided the Hydrochloride inisolated form.

[0015] In a further aspect there is provided the Hydrochloride in pureform.

[0016] In yet a further aspect there is provided the Hydrochloride incrystalline form.

[0017] As indicated above the Hydrochloride is non-hygroscopic. Theinvention further includes substantially non-hydrated andnon-hygroscopic (or slightly hygroscopic) hydrochloride salts of5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione.

[0018] The invention also provides a process for preparing theHydrochloride, characterised in that5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione(Compound I) or a salt thereof, preferably dispersed or dissolved in asuitable solvent, is reacted with a source of hydrogen chloride; andthereafter the Hydrochloride is recovered.

[0019] Preferably, the reaction is carried out under anhydrousconditions, for example in a dried nitrogen atmosphere.

[0020] A suitable solvent is an alkanol, for example propan-2-ol, or ahydrocarbon, such as toluene, a ketone, such as acetone, an ester, suchas ethyl acetate, an ether such as tetrahydrofuran, a nitrile such asacetonitrile, or a halogenated hydrocarbon such as dichloromethane.

[0021] Conveniently, the source of hydrogen chloride is a solution ofhydrogen chloride in an appropriate solvent, usually the reactionsolvent, for example propan-2-ol. Alternatively, the source of hydrogenchloride may be provided by concentrated hydrochloric acid or aqueousdilutions of concentrated hydrochloric acid which are suitably dilutedso as to provide the required product, although concentratedhydrochloric acid is preferred.

[0022] It is considered that the Hydrochloride can be produced in theabove mentioned reactions in the presence of small amounts of water butas stated the reaction is preferably carried out under anhydrousconditions.

[0023] The reaction is usually carried out at ambient temperature or atan elevated temperature, although any convenient temperature thatprovides the required product may be employed. A preferred temperatureis in the range of from 20-120° C., such as 30° C. to 80° C., forexample 70° C.

[0024] Recovery of the required compound generally comprisescrystallisation from an appropriate solvent, conveniently the reactionsolvent, usually by cooling to a temperature in the range of from 0° C.to 40° C., for example 20° C.

[0025] In one preferred form the recovery comprises initial cooling to afirst temperature, such as 35° C. to 70° C., preferably 50° C. to 60°C., thereby allowing initiating crystallisation and thereafter coolingto a second temperature, suitably in the range of 0° C. to 40° C., tocomplete crystallisation.

[0026] Crystallisation can also be initiated by seeding with crystals ofthe Hydrochloride but this is not essential.

[0027] Compound I is prepared according to known procedures, such asthose disclosed in EP 0,306,228 and WO94/05659. The disclosures of EP0,306,228 and WO94/05659 are incorporated herein by reference.

[0028] When used herein the term prophylaxis of conditions associatedwith diabetes mellitus' includes the treatment of conditions such asinsulin resistance, impaired glucose tolerance, hyperinsulinaemia andgestational diabetes.

[0029] When used herein the terms relating to hygroscopicity are used inaccordance with known criteria as set out in J C Callahan et al., DrugDevelopment and Industrial Pharmacy, 1982, 8(3), 355-69 which classifieshygroscopicity with respect to the % weight gain of a test compoundunder controlled conditions of temperature and humidity (25° C. and 75%relative humidity) wherein the test compound has been allowed to attainan approximately constant weight: the following classification is used:% Weight Gain Classification   <2% non-hygroscopic  2-10% slightlyhygroscopic 10-20% moderately hygroscopic  >20% very hygroscopic

[0030] For the avoidance of doubt when used herein the terms“non-hygroscopic”, “slightly hygroscopic”, “moderately hygroscopic” and“very hygroscopic” are to have the meanings defined by the abovementioned criteria.

[0031] Furthermore, the term “slightly hygroscopic” can particularlymean a compound showing a % weight gain under the above mentionedcriteria of any one of 2-9%. 2-8%, 2-7%, 2-6%, 2-5%, 2-4% and 2-3%.

[0032] Diabetes mellitus preferably means Type II diabetes mellitus.

[0033] Conditions associated with diabetes include hyperglycaemia andinsulin resistance and obesity. Further conditions associated withdiabetes include hypertension, cardiovascular disease, especiallyatherosclerosis, certain eating disorders, in particular the regulationof appetite and food intake in subjects suffering from disordersassociated with under-eating, such as anorexia nervosa, and disordersassociated with over-eating, such as obesity and anorexia bulimia.Additional conditions associated with diabetes include polycysticovarian syndrome and steroid induced insulin resistance.

[0034] The complications of conditions associated with diabetes mellitusencompassed herein includes renal disease, especially renal diseaseassociated with the development of Type II diabetes including diabeticnephropathy, glomerulonephritis, glomerular sclerosis, nephroticsyndrome, hypertensive nephrosclerosis and end stage renal disease.

[0035] As mentioned above the compound of the invention has usefultherapeutic properties: The present invention accordingly provides theHydrochloride for use as an active therapeutic substance.

[0036] More particularly, the present invention provides theHydrochloride for use in the treatment and/or prophylaxis of diabetesmellitus, conditions associated with diabetes mellitus and certaincomplications thereof.

[0037] Hydrochloride may be administered per se or, preferably, as apharmaceutical composition also comprising a pharmaceutically acceptablecarrier. The formulation of the Hydrochloride is generally as disclosedfor Compound I in the above mentioned publications.

[0038] Accordingly, the present invention also provides a pharmaceuticalcomposition comprising the Hydrochloride and a pharmaceuticallyacceptable carrier therefor.

[0039] The Hydrochloride is normally administered in unit dosage form.

[0040] The active compound may be administered by any suitable route butusually by the oral or parenteral routes. For such use, the compoundwill normally be employed in the form of a pharmaceutical composition inassociation with a pharmaceutical carrier, diluent and/or excipient,although the exact form of the composition will naturally depend on themode of administration.

[0041] Compositions are prepared by admixture and are suitably adaptedfor oral, parenteral or topical administration, and as such may be inthe form of tablets, capsules, oral liquid preparations, powders,granules, lozenges, pastilles, reconstitutable powders, injectable andinfusable solutions or suspensions, suppositories and transdermaldevices. Orally administrable compositions are preferred, in particularshaped oral compositions, since they are more convenient for generaluse.

[0042] Tablets and capsules for oral administration are usuallypresented in a unit dose, and contain conventional excipients such asbinding agents, fillers, diluents, tabletting agents, lubricants,disintegrants, colourants, flavourings, and wetting agents. The tabletsmay be coated according to well known methods in the art.

[0043] Suitable fillers for use include cellulose, mannitol, lactose andother similar agents. Suitable disintegrants include starch,polyvinylpyrrolidone and starch derivatives such as sodium starchglycollate. Suitable lubricants include, for example, magnesiumstearate. Suitable pharmaceutically acceptable wetting agents includesodium lauryl sulphate.

[0044] Solid oral compositions may be prepared by conventional methodsof blending, filling, tabletting or the like. Repeated blendingoperations may be used to distribute the active agent throughout thosecompositions employing large quantities of fillers. Such operations are,of course, conventional in the art.

[0045] Oral liquid preparations may be in the form of, for example,aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs,or may be presented as a dry product for reconstitution with water orother suitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asesters of glycerine, propylene glycol, or ethyl alcohol; preservatives,for example methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

[0046] For parenteral administration, fluid unit dose forms are preparedcontaining a compound of the present invention and a sterile vehicle.The compound, depending on the vehicle and the concentration, can beeither suspended or dissolved. Parenteral solutions are normallyprepared by dissolving the active compound in a vehicle and filtersterilising before filling into a suitable vial or ampoule and sealing.Advantageously, adjuvants such as a local anaesthetic, preservatives andbuffering agents are also dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum.

[0047] Parenteral suspensions are prepared in substantially the samemanner except that the active compound is suspended in the vehicleinstead of being dissolved and sterilised by exposure to ethylene oxidebefore suspending in the sterile vehicle. Advantageously, a surfactantor wetting agent is included in the composition to facilitate uniformdistribution of the active compound.

[0048] As is common practice, the compositions will usually beaccompanied by written or printed directions for use in the medicaltreatment concerned.

[0049] As used herein the term ‘pharmaceutically acceptable’ embracescompounds, compositions and ingredients for both human and veterinaryuse: for example the term ‘pharmaceutically acceptable salt’ embraces aveterinarily acceptable salt.

[0050] The present invention further provides a method for the treatmentand/or prophylaxis of diabetes mellitus, conditions associated withdiabetes mellitus and certain complications thereof, in a human ornon-human mammal which comprises administering an effective, non-toxic,amount of Hydrochloride to a human or non-human mammal in need thereof.

[0051] Conveniently, the active ingredient may be administered as apharmaceutical composition hereinbefore defined, and this forms aparticular aspect of the present invention.

[0052] In a further aspect the present invention provides the use ofHydrochloride for the manufacture of a medicament for the treatmentand/or prophylaxis of diabetes mellitus, conditions associated withdiabetes mellitus and certain complications thereof.

[0053] In the treatment and/or prophylaxis of diabetes mellitus,conditions associated with diabetes mellitus and certain complicationsthereof the Hydrochloride may be taken in amounts so as to provideCompound I in suitable doses, such as those disclosed in EP 0,306,228and WO94/05659.

[0054] No adverse toxicological effects are indicated in the abovementioned treatments for the compounds of the invention.

[0055] The following examples illustrate the invention but do not limitit in any way.

EXAMPLE 1 Preparation of5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dionehydrochloride

[0056] A mixture of5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione(6.0 g) and propan-2-ol (120 ml) was stirred and heated to 50° C. undera nitrogen atmosphere. A solution of hydrogen chloride in propan-2-ol(5-6 N, 5.0 ml) was added and the stirred mixture warmed to 70° C., atwhich point a clear solution was observed. After cooling to 45° C. overa period of one hour the resulting cloudy solution was warmed to 60° C.and maintained at this temperature for a period of 1 hour. The resultingthick white suspension was cooled to 30° C. and the solid productcollected by filtration, washed with propan-2-ol (25 ml) and dried undervacuum, over phosphorus pentoxide for 16 hours to give the titlecompound as a white crystalline solid (5.7 g).

[0057] Melting point 168-170° C.

[0058] DSC: T_(onset)=166.6° C., T_(peak)=169.5° C. Elemental Analysis:Found: C; 54.88 H; 5.16 N; 10.56 Theory: (C₁₈H₂₀N₃O₃SCl) C; 54.89 H;5.12 N; 10.67

[0059] Ionic chlorine: Determined as 9.0% wt/wt (theory forC₁₈H₂₀N₃O₃SCl: 9.0% wt/wt).

[0060] Water content: Determined as 0.2% wt/wt using a Karl Fischerapparatus.

EXAMPLE 2 Preparation of5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dionehydrochloride

[0061] A mixture of5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione(4.0 g) and propan-2-ol (100 ml) was stirred and heated to 70° C.Concentrated hydrochloric acid (1.1 ml) was added to the stirredreaction mixture which was observed to give a clear solution afterapproximately 3 minutes. The stirred solution was cooled to 58° C. andthen maintained at a temperature between 58-60° C. for 1 hour. Theresulting white suspension was cooled to 30° C. and the solid productcollected by filtration, washed with propan-2-ol (20 ml) and dried undervacuum over phosphorus pentoxide for 64 hours to give the title compoundas a white crystalline solid (4.3 g).

[0062] Hygroscopicity of the Hydrochloride

[0063] A sample of the hydrochloride salt (279 mg), prepared accordingto Example 1, was exposed to a 75% relative humidity atmosphere at 21°C. for a period of 43 days. The sample attained constant weight duringthis period. The percentage weight gain of the sample was observed to be0.4%.

CONCLUSION

[0064] The hydrochloride salt is non-hygroscopic.

[0065] Aqueous Stability and Solubility of the Hydrochloride

[0066] 50 mg of the salt was placed in a 20 mL volumetric flask, andwater added in 2.5 mL aliquots. The sample was ultrasonicated at 21° C.to aid dissolution after each subsequent addition of water and thenexamined. When a clear solution was obtained, the approximate solubilitymg/mL was calculated. The solution was then examined at hourly intervalsfor evidence of subsequent clouding or precipitation. Water added total(mL) Observation 2.5 mL Cloudy suspension 5.0 mL Predominantly clear,only partially cloudy 7.5 mL Clear solution obtained. Remained clearafter standing at 21° C. for a further 2 hours. Approx. solubility 7mg/mL

CONCLUSION

[0067] The white crystalline solid dissolved readily to give a clearsolution with a good aqueous solubility. The solution subsequentlyremained clear with no evidence of precipitation or clouding of thesolution. This data confirms a previous experiment on a different batchof the Hydrochloride that also evidenced good solubility and provided aclear solution with no evidence of precipitation or clouding of thesolution

[0068] Characterising data recorded for the product of Example 1:

[0069] A Infrared

[0070] The IR spectrum (FIG. I) was recorded as a liquid paraffin mullusing a Perkin-Elmer 1720× FTIR instrument at a resolution of 2 cm-1.The spectrum obtained is shown in FIG. 1. Bands were observed at:

[0071] 1745, 1696, 1641, 1609, 1544, 1516, 1331, 1313, 1289, 1257, 1243,1230, 1203, 1185, 1157, 1073, 1056, 1032, 1015, 984, 918, 907, 873, 841,811, 803, 772, 738, 714, 657, 618, 605, 560, 527 and 505 cm⁻¹.

[0072] B X-Ray Powder Diffraction (XRPD)

[0073] The XRPD pattern of the Hydrochloride (FIG. II) was recordedusing a using the following acquisition conditions: Tube anode: Cu,Generator tension: 40 kV, Generator current: 40 mA, Start angle: 2.0°2θ, End angle: 35.0 °2θ, Step size: 0.02 °2θ, Time per step: 10.0seconds.

[0074] Characteristic XRPD angles and relative intensities are recordedin Table I. TABLE I Diffraction Relative Angle Intensity (° 2θ) (%) 10.14.9 11.8 15.2 12.4 8.1 13.4 24.7 14.0 4.5 14.6 2.6 15.0 10 16.1 38.216.3 91.6 17.2 28 17.7 69 18.1 49.5 19.3 14.2 19.6 46.1 20.4 14.2 20.96.9 21.2 24.9 22.2 100 22.4 72.5 22.7 36.4 23.6 98.2 23.8 79.8 24.8 49.125.5 10.6 26.1 18.9 26.4 35.9 27.1 35.2 27.4 22.9 28.1 32.6 29.4 32.930.0 18.8 30.6 21.4 31.1 11.8 32.1 20 32.6 20.5 33.0 19.8 33.9 23.5 34.529.6

[0075] C Raman

[0076] The Raman spectrum (FIG. III) was recorded with the sample in aglass vial in a Perkin-Elmer 2000R FT-Raman system, at 4 cm⁻¹resolution. Excitation was from a Nd:YAG laser (1064 nm) with a poweroutput of 400 mW. Bands were observed at:

[0077] 3100,3068,2927,2893,2863, 1746,1706, 1611, 1587, 1545, 1446,1382, 1360, 1314, 1287, 1242, 1212, 1185, 1156, 1096, 1073, 1032,1017,984,918,828, 772,741,715, 659, 636, 619, 606, 527, 506, 471, 440,404, 333, 302, 262 cm⁻¹.

1. A substantially non-hydrated and non-hygroscopic or slightlyhygroscopic hydrochloride salts of 5-[4-[2-(N-methyl-N-(2pyridyl)amino)ethoxy]benzyl]thiazolidine-2.4-dione.
 2. A compound5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,hydrochloride characterised in that it: (i) provides an infraredspectrum containing peaks at about 1745, 1516, 1257, 1056 and 803 cm⁻¹;(ii) provides an X-ray powder diffraction (XRPD) pattern containingpeaks at about 10.1, 13.4, 17.2, 22.2 and 29.4 °2θ; and/or (iii)provides a Raman spectrum containing peaks at about 1314, 1242, 1185,918 and 404 cm⁻¹.
 3. A compound according to claim 2, wherein theHydrochloride provides an infrared spectrum substantially in accordancewith FIG. I.
 4. A compound according to claim 2 or claim 3, wherein theHydrochloride provides an X-Ray powder diffraction pattern (XRPD)substantially in accordance with FIG. II.
 5. A compound according to anyone of claims 2 to 4, wherein the Hydrochloride provides a ramanspectrum substantially in accordance with FIG. III.
 6. A process forpreparing the Hydrochloride according to claim 1, characterised in that5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione(Compound I) or a salt thereof, preferably dispersed or dissolved in asuitable solvent, is reacted with a source of hydrogen chloride; andthereafter the Hydrochloride is recovered.
 7. A process according toclaim 6, wherein the reaction is carried out under anhydrous conditions.8. A compound according to any one of claims 1 to 5, for use as anactive therapeutic substance.
 9. A compound according to any one ofclaims 1 to 5, for use in the treatment and/or prophylaxis of diabetesmellitus, conditions associated with diabetes mellitus and certaincomplications thereof.
 10. A pharmaceutical composition comprising theHydrochloride and a pharmaceutically acceptable carrier therefor.